This R01 application from Memorial Sloan-Kettering Cancer Center is founded on recent work spearheaded by the MPIs Professor Jason Lewis and Dr. Michael Evans in close collaboration with basic science and clinical investigators. Based on the evocative preliminary data, the central hypothesis is that the novel radiotracer 89Zr- labeled transferrin (89Zr-Tf) will be a non-invasive tool for the staging and management of prostate cancer. What distinguishes this radiotracer from its contemporaries (18F-FDG, 18F-FACBC, ProstascintTM) is that it systematically targets a tumor associated protein (the transferrin receptor [TFRC]) whose expression and bioactivity is directly linked to the pathological activation of MYC or PI3K-two oncogenes deeply relevant to the pathogenesis of prostate cancer. To address our hypothesis three Specific Aims have been proposed; Specific Aim 1 (SA1) intends to establish that 89Zr-Tf can measure the changes in MYC signaling required to confer a tumor response to JQ1, an inhibitor of the epigenetic protein BRD4 (and MYC); Specific Aim 2 (SA2) intends to show that 89Zr-Tf can measure aberrant PI3K signaling in prostate cancer and monitor tumor response to targeted therapies; and, Specific Aim 3 (SA3) proposes to conduct first-in-human studies (Phase 0) of 89Zr-Tf in newly diagnosed prostate cancer to initiate a larger clinical program to evaluate the many potential applications for 89Zr-T in man. The innovation of this proposal derives from the original design of 89Zr-Tf. By invoking a clear biological mandate for its development (i.e. the straightforward functional relationship between TFRC and MYC or PI3K), the application of 89Zr-Tf extends beyond the detection of a gross tumor property to measuring the degree of signaling through two important oncogenic pathways. Moreover, the exceptional pharmacokinetics of 89Zr-Tf clearly distinguishes it from other clinically validated technologies targeting the transferrin receptor (67Ga-citrate). These considerations directly influence the impact of the proposal, as we respectfully submit that we may answer at least three questions related to fundamentally important themes in cancer diagnostics: (1) does the basal uptake of 89Zr-Tf quantitatively distinguish tumors bearing pathological activation of MYC and/or PI3K signaling (prognostic biomarker development), (2) do post-therapy changes in 89Zr-Tf uptake measure target inhibition (drug pharmaco- dynamics and clinical trial endpoints), and (3) can 89Zr-Tf more clearly distinguish tumor topography and dissemination in newly diagnosed prostate cancer (accurate staging and treatment planning). If successful this PET agent could cause a significant paradigm shift in radiotracer development strategies and the diagnosis and management of prostate cancer in man.